(1) Field of the Invention
The present invention relates to a process for the preparation of 2-amino-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)adenine (V) and certain novel intermediate compounds which are useful in the preparation of 2-fluoro-ara-AMP, a cytotoxic agent. In particular the present invention relates to a process wherein a protected compound 2,6-di(alkoxyacetamido)purine (II) is reacted with 2,3,5-tri-O-benzyl-alpha-D-arabinofuranosyl chloride (III) to produce 2,6-di(alkoxyacetamido)-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl)puri ne (IV) and then the alkoxyacetyl groups are removed to produce the title sugar-protected compound V in high yield.
(2) Prior Art
Example 2B of U.S. Pat. No. 4,188,378 (Feb. 12, 1980) to John A. Montgomery shows the preparation of 2-amino-9-(2,3,5-tri-O-benzyl-beta-D-arabinofuranosyl) adenine (V). To accomplish this 2,3,5-tri-O-benzyl-1-O-p-nitrobenzoyl-beta-D-arabinofuranose was converted to the furanosyl chloride (III) in ethylene chloride and reacted with 2,6-diacetamidopurine (II). The resulting intermediate (IV) was then treated with sodium methoxide in methanol to remove the two acetyl groups and produce the target 2-aminoadenine (V) in 34% yield overall. This is the same route reported earlier by Montgomery et al. in J. Hetero. Chem. 16, 157 (1979), in which the reported overall yield was 40%. This method is clearly a low yield process. In example 2A of the cited patent, Montgomery prepared Compound (V) by an alternative sequence of reactions. These involved the prior preparation (not shown) of 2,6-dichloropurine which was then treated with sodium azide in ethanol to yield the 2,6-diazidopurine as described in Example 1. This was followed by catalytic hydrogenation to obtain Compound (V). This is clearly a longer, less desirable route.